Plasma miRNA Levels for Predicting Therapeutic Response to Neoadjuvant Treatment in HER2-positive Breast Cancer: Results from the NeoALTTO Trial.

Published on Jul 1, 2019in Clinical Cancer Research10.107
· DOI :10.1158/1078-0432.CCR-18-2507
Serena Di Cosimo31
Estimated H-index: 31
Valentina Appierto16
Estimated H-index: 16
+ 13 AuthorsMaria Grazia Daidone72
Estimated H-index: 72
Purpose: To investigate the potential of circulating-microRNAs (ct-miRNAs) as non-invasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study. Experimental Design: Patients with plasma samples at baseline (T0) and/or after two weeks (T1) of treatment were randomized into training (n=183) and testing (n=246) sets. RT-PCR-based high-throughput miRNA-profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic Complete Response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-Free-Survival (EFS) according to ct-miRNA signatures was estimated by Kaplan-Meier method and Cox regression model. Results: In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of Area Under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: Lapatinib at T0 and T1, (AUC 0.86 [95%CI 0.73-0.98] and 0.71 [0.55-0.86]), respectively; Trastuzumab at T1 (0.81 [0.70-0.92]); Lapatinib+Trastuzumab at T1 (0.67 [0.51-0.83]). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the Trastuzumab signature, were associated with EFS (HR 0.43; 95%CI:0.22-0.84). Conclusions: ct-miRNAs discriminate patients with and without pCR after neoadjuvant Lapatinib- and/or Trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to Trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist de-escalating treatment strategies.
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